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Updates found with 'dna nanorobots'

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Updates found with 'dna nanorobots'

Sequencing Human Genome with Pocket-Sized “Nanopore” DeviceDr. Francis CollinsMinION sequencing deviceIt’s hard to believe, but it’s been almost 15 years since we successfully completed the Human Genome Project, ahead of schedule and under budget. I was proud to stand with my international colleagues in a celebration at the Library of Congress on April 14, 2003 (which happens to be my birthday), to announce that we had stitched together the very first reference sequence of the human genome at a total cost of about $400 million. As remarkable as that achievement was, it was just the beginning of our ongoing effort to understand the human genome, and to use that understanding to improve human health.That first reference human genome was sequenced using automated machines that were the size of small phone booths. Since then, breathtaking progress has been made in developing innovative technologies that have made DNA sequencing far easier, faster, and more affordable. Now, a report in Nature Biotechnology highlights the latest advance: the sequencing and assembly of a human genome using a pocket-sized device [1]. It was generated using several “nanopore” devices that can be purchased online with a “starter kit” for just $1, 000. In fact, this new genome sequence—completed in a matter of weeks—includes some notoriously hard-to-sequence stretches of DNA, filling several key gaps in our original reference genome.For most sequencing methods, DNA must be broken into smaller, more manageable fragments. That means all of the nucleotide “letters”— the As, Cs, Gs, and Ts—in the DNA code must be pieced back together in their correct order like a complex puzzle. While many methods are incredibly accurate at reassembling many parts of the puzzle, it’s much trickier to do this in highly repetitive stretches of DNA. When broken up, they produce puzzle pieces that are essentially identical.To get around that problem, some newer sequencing technologies are able to read out much longer stretches of DNA. In this latest report, an international team including Nicholas Loman at the University of Birmingham in the United Kingdom (U.K.), Matthew Loose at the University of Nottingham, U.K., and Adam Phillippy at NIH’s National Human Genome Research Institute, Bethesda, MD, relied on one such device: the hand-held MinION nanopore sequencer, produced by Oxford Nanopore Technologies.In fact, nanopore sequencing was named one of Science magazine’s “Breakthroughs of the Year” in 2016. The method involves threading single DNA strands through many tiny protein pores, i.e., nanopores, set in an electrically resistant polymer membrane. Inside the device, an ionic current is passed through the nanopore. When a single-stranded DNA molecule passes through the charged nanopore, it alters the current. In fact, the current is altered in different ways depending on which of DNA’s four unique nucletoides—adenine (A), cytosine (C), guanine (G), or thymine (T)—is passing through the pore. As a result, it’s possible to “read” off the DNA sequence, letter by letter!The nanopore sequencer was initially used primarily for sequencing smaller microbial genomes. In fact, Loman was part of a team that used the portable nanopore device to track Ebola and Zika viruses during the recent outbreaks in Africa and Brazil [2, 3]. The nanopore sequencer was also used on the International Space Station to do the very first DNA sequencing in zero gravity [4].The larger, more complex human genome represents a much stiffer challenge. But Loman and colleagues took on the challenge, betting that MinION was now up to the task based on recent improvements in its sequencing speed, computer software, and sample prep.The team, which included five labs in three countries, sequenced the complete genome of a well-studied human cell line in a matter of weeks. The researchers generated 91.2 gigabytes of DNA data, enough to cover the genome 30 times over, which helps to put the pieces together accurately. Most notably, they also generated ultra-long “reads” up to 882, 000 bases of contiguous DNA sequence. The researchers report that they have since read individual DNA molecules over a million bases long! Though the final cost ran about $23, 000 to sequence one human genome, further refinements should continue to drop the price.The real trick to getting such long reads is to prepare the DNA in such a way that the molecules don’t get cut or otherwise broken into small fragments, which the team has learned to do well. In fact, the team reports that in principle there may be no limit to the read-lengths that are possible using nanopore-based sequencing, including possibly entire chromosomes. The challenge will be getting the DNA molecules into the sequencing device without damaging them. Once a DNA molecule is threaded into a pore, there’s really no reason for it to stop until its passed all the way through.Despite those longer, easier-to-assemble reads, the researchers still required some big computers, including the high-performance computational resources in NIH’s Biowulf system, to make sense of the data, correct for errors, and piece together portions of the genome that had been impossible to assemble previously. For example, they resolved several highly repetitive genomic regions, including the sequences of some essential genes in immunity. They were also able to accurately estimate the lengths of highly repetitive telomeres, which act like “caps” at the tips of chromosomes. Telomere lengths are of great research interest for their implications in aging and cancer.Just as capabilities once only available through huge supercomputers can today be accessed though apps on smartphones, DNA sequencers continue to get better, smaller, and more portable. And as this study demonstrates, there’s no doubt that we’re pushing ever closer to a time when it may become both feasible and practical to sequence individual human genomes to bring greater precision to the delivery of health care for everyone.References:[1] Nanopore sequencing and assembly of a human genome with ultra-long reads. Jain M, Koren S, Miga KH, Quick J, Rand AC, Sasani TA, Tyson JR, Beggs AD, Dilthey AT, Fiddes IT, Malla S, Marriott H, Nieto T, O’Grady J, Olsen HE, Pedersen BS, Rhie A, Richardson H, Quinlan AR, Snutch TP, Tee L, Paten B, Phillippy AM, Simpson JT, Loman NJ, Loose M. Nature Biotech. 2018 Jan. 29. [Epub ahead of print][2] Real-time, portable genome sequencing for Ebola surveillance. Quick J, Loman NJ, Duraffour S, Simpson JT, Severi E, Cowley L, et al..Nature. 2016 Feb 11;530(7589):228-232.[3] Establishment and cryptic transmission of Zika virus in Brazil and the Americas. Faria NR, Quick J, Claro IM, Thézé J, de Jesus JG, et al. Nature. 2017 Jun 15;546(7658):406-410.[4] Nanopore DNA Sequencing and Genome Assembly on the International Space Station. Castro-Wallace SL, Chiu CY, John KK, Stahl SE, Rubins KH, McIntyre ABR, Dworkin JP, Lupisella ML, Smith DJ, Botkin DJ, Stephenson TA, Juul S, Turner DJ, Izquierdo F, Federman S, Stryke D, Somasekar S, Alexander N, Yu G, Mason CE7, Burton AS. Sci Rep. 2017 Dec 21;7(1):18022.Links:DNA Sequencing (National Human Genome Research Institute/NIH)Loman Lab (University of Birmingham, United Kingdom)Matt Loose (University of Nottingham, U.K.)Adam Phillippy (National Human Genome Research Institute/NIH)MinION (Oxford Nanopore Technologies, U.K.)NIH Support: National Human Genome Research Institute; National Cancer Institute
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New DNA nanorobots successfully target and kill off cancerous tumorsBY SARAH BUHRFeb 12, 2018Science fiction no more — in an article out today in Nature Biotechnology, scientists were able to show tiny autonomous bots have the potential to function as intelligent delivery vehicles to cure cancer in mice.These DNA nanorobots do so by seeking out and injecting cancerous tumors with drugs that can cut off their blood supply, shriveling them up and killing them.“Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth, ” the paper explains.DNA nanorobots are a somewhat new concept for drug delivery. They work by getting programmed DNA to fold into itself like origami and then deploying it like a tiny machine, ready for action.DNA nanorobots, Nature Biotechnology 2018The scientists behind this study tested the delivery bots by injecting them into mice with human breast cancer tumors. Within 48 hours, the bots had successfully grabbed onto vascular cells at the tumor sites, causing blood clots in the tumor’s vessels and cutting off their blood supply, leading to their death.Remarkably, the bots did not cause clotting in other parts of the body, just the cancerous cells they’d been programmed to target, according to the paper.The scientists were also able to demonstrate the bots did not cause clotting in the healthy tissues of Bama miniature pigs, calming fears over what might happen in larger animals.The goal, say the scientists behind the paper, is to eventually prove these bots can do the same thing in humans. Of course, more work will need to be done before human trials begin.Regardless, this is a huge breakthrough in cancer research. The current methods of either using chemotherapy to destroy every cell just to get at the cancer cell are barbaric in comparison. Using targeted drugs is also not as exact as simply cutting off blood supply and killing the cancer on the spot. Should this new technique gain approval for use on humans in the near future it could have impressive affects on those afflicted with the disease
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Newswise — As a basic unit of life, the cell is one of the most carefully studied components of all living organisms. Yet details on basic processes such as how cells are shaped have remained a mystery. Working at the intersection of biology and physics, scientists at the University of California San Diego have made an unexpected discovery at the root of cell formation.As reported in the journal Cell on Feb. 8, 2018, biologists Javier Lopez-Garrido, Kit Pogliano and their colleagues at UC San Diego and Imperial College in London found that DNA executes an unexpected architectural role in shaping the cells of bacteria.Studying the bacterium Bacillus subtilis, the researchers used an array of experiments and technologies to reveal that DNA, beyond serving to encode genetic information, also “pumps up” bacterial cells.“Our study illustrates that DNA acts like air in a balloon, inflating the cell, ” said Lopez-Garrido, an assistant research scientist in UC San Diego’s Division of Biological Sciences and the study’s first author. “DNA is best known for being the molecule with genetic information but it’s becoming more and more obvious that it does other things that are not related to that.”The researchers say the results could have relevance in human cells in terms of how they are generated and shaped, as well as aid explanations of basic mechanical processes and the structure of the nucleus and mitochondria. The results could also allow scientists to have a glimpse into the origins of cellular life itself. Modern bacterial cells have evolved a variety of mechanisms to control their internal pressure, said Lopez-Garrido. However, those mechanisms were absent in primitive cells at the dawn of life on earth. The finding that DNA can inflate a cell might allow scientists to achieve a better understanding of the physiology of the first cells on the planet.“Biologists tend to think of cell growth as following normal, biosynthetic pathways, but we found a pathway that is not normal, as it does not depend on processes normally required for growth, ” said Pogliano, a professor in the Section of Molecular Biology and the paper’s senior author. “All you need for this cell to grow is to inflate it with DNA and its associated positively charged ions, and the ability to make more membrane so the cell can get bigger. Nothing else seems to be required.”The researchers employed time-lapse fluorescent microscopy to methodically track cell formation in Bacillus subtilis through a process known as sporulation. During this process cells split into a mother cell and a smaller cell, or forespore. Also using cryo-electron tomography to capture extreme close-ups of the process unfolding, the researchers witnessed the mother cells inflating the forespore with DNA in a stretching and swelling process, ultimately leading to a new, egg-shaped cell.“It’s amazing how we are just beginning to scratch the surface of how physics impacts living organisms, ” said Pogliano. “This is a unique example of a very simple biophysical property impacting cell shape and it illustrates the value of physicists working closely with biologists. Understanding how physics and biology intersect is a huge area for future growth.”Coauthors of the study include Nikola Ojkic and Robert Endres of Imperial College; and Kanika Khanna, Felix Wagner and Elizabeth Villa of UC San Diego.Funding was provided by the European Research Council (starting grant 280492-PPHPI), National Institutes of Health (grant R01-GM57045), NIH Director’s New Innovator Award (1DP2GM123494-01) and a European Molecular Biology Organization (EMBO) Long Term Fellowship (ALTF 1274-2011). The researchers used the UC San Diego Cryo-EM Facility (supported by NIH grant R01-GM33050) and the San Diego Nanotechnology Infrastructure of UC San Diego (supported by National Science Foundation grant ECCS-1542148).
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In the future we won’t edit genomes—we’ll just print out new onesWhy redesigning the humble yeast could kick off the next industrial revolution.by Bryan Walsh February 16, 2018At least since thirsty Sumerians began brewing beer thousands of years ago, Homo sapiens has had a tight relationship with Saccharomyces cerevisiae, the unicellular fungus better known as brewer’s yeast. Through fermentation, humans were able to harness a microscopic species for our own ends. These days yeast cells produce ethanol and insulin and are the workhorse of science labs.That doesn’t mean S. cerevisiae can’t be further improved—at least not if Jef Boeke has his way. The director of the Institute for Systems Genetics at New York University’s Langone Health, Boeke is leading an international team of hundreds dedicated to synthesizing the 12.5 million genetic letters that make up a yeast’s cells genome.In practice, that means gradually replacing each yeast chromosome—there are 16 of them—with DNA fabricated on stove-size chemical synthesizers. As they go, Boeke and collaborators at nearly a dozen institutions are streamlining the yeast genome and putting in back doors to let researchers shuffle its genes at will. In the end, the synthetic yeast—called Sc2.0—will be fully customizable.“Over the next 10 years synthetic biology is going to be producing all kinds of compounds and materials with microorganisms, ” says Boeke. “We hope that our yeast is going to play a big role in that.”Think of the project as something like Henry Ford’s first automobile—hand built and, for now, one of a kind. One day, though, we may routinely design genomes on computer screens. Instead of engineering or even editing the DNA of an organism, it could become easier to just print out a fresh copy. Imagine designer algae that make fuel; disease-proof organs; even extinct species resurrected.Jef Boeke leads an effort to create yeast with a man-made genome.“I think this could be bigger than the space revolution or the computer revolution, ” says George Church, a genome scientist at Harvard Medical School.Researchers have previously synthesized the genetic instructions that operate viruses and bacteria. But yeast cells are eukaryotic—meaning they confine their genomes in a nucleus and bundle them in chromosomes, just as humans do. Their genomes are also much bigger.That’s a problem because synthesizing DNA is still nowhere near as cheap as reading it. A human genome can now be sequenced for $1, 000, with the cost still falling. By comparison, to replace every DNA letter in yeast, Boeke will have to buy $1.25 million worth of it. Add labor and computer power, and the total cost of the project, already under way for a decade, is considerably more.Along with Church, among others, Boeke is a leader of GP-write, an organization advocating for international research to reduce the cost of designing, engineering, and testing genomes by a factor of a thousand over the next decade. “We have all kinds of challenges facing ourselves as a species on this planet, and biology could have a huge impact on them, ” he says. “But only if we can drive down costs.”Bottom upA scientist named Ronald Davis at Stanford first suggested the possibility of synthesizing the yeast genome at a conference in 2004—though initially, Boeke didn’t see the point. “Why would anyone want to do this?” he recalls thinking.But Boeke came around to the idea that manufacturing a yeast genome might be the best way to comprehend the organism. By replacing each part, you might learn which genes are necessary and which the organism can live without. Some team members call the idea “build to understand.”“It’s a different take on trying to understand how living things work, ” says Leslie Mitchell, a postdoctoral fellow in the NYU lab and one of the main designers of the synthetic yeast. “We learn what gaps in our knowledge exist in a bottom-up genetic approach.”Joel Bader, a computer scientist at Johns Hopkins, signed on to develop software that let scientists see the yeast chromosomes on a screen and keep track of versions as they changed, like a Google Docs for biology. And in 2008, to make the DNA, Boeke launched an undergraduate course at Hopkins called “Build a Genome.” Students would learn basic molecular biology as each one assembled a continuous stretch of 10, 000 DNA letters that would go toward the synthetic-yeast project. Later, several institutions in China joined to share the workload, along with collaborators in Britain, Australia, and Japan.“We assign chromosomes to individual teams, like assigning a chapter of a book, and they have the freedom to decide how to do it, as long as it’s based 100 percent on what we design, ” says Patrick Cai, a synthetic biologist at the University of Manchester and the yeast project’s international coordinator.Next stepsIt took Boeke and his team eight years before they were able to publish their first fully artificial yeast chromosome. The project has since accelerated. Last March, the next five synthetic yeast chromosomes were described in a suite of papers in Science, and Boeke says that all 16 chromosomes are now at least 80 percent done. These efforts represent the largest amount of genetic material ever synthesized and then joined together.It helps that the yeast genome has proved remarkably resilient to the team’s visions and revisions. “Probably the biggest headline here is that you can torture the genome in a multitude of different ways, and the yeast just laughs, ” says Boeke.
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IGIB researchers partially reverse a rare disorderThe HinduR. Prasad10 FEBRUARY 2018 18:13 ISTUPDATED: 10 FEBRUARY 2018 18:14 IST The syndrome also affects about one in one lakh people, causing a range of defectResearchers at Delhi’s Institute of Genomics & Integrative Biology (CSIR-IGIB) have for the first time used zebra fish to model the rare genetic disorder — Rubinstein Taybi Syndrome (RSTS) — seen in humans. They have also used two small molecules to partially reverse some of the defects caused by the disorder in zebrafish, thus showing them to be an ideal animal model for screening drug candidates. There is currently no cure or treatment for the disorder.The Rubinstein Taybi Syndrome has a frequency of about one in one lakh people, and causes intellectual disability, growth retardation (short stature), craniofacial deformities, heart defects and broad thumbs and toes. The results were published in the journal Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.Close to human genomeSince zebrafish genome has very close similarity to human genome and the embryonic developmental is very similar in the two, the team led by Dr. Chetana Sachidanandan at IGIB went about checking if EP300, one of the two genes that cause the disorder is present in the fish and if mutations in this gene result in a RSTS-like disease in fish.Using chemicals, the researchers inhibited the activity of the protein Ep300 to see if this resulted in the manifestation of the disorder in the brain, heart, face and pectoral fins (equivalent to forearm in humans). “Like in the case of humans, the same organs were affected in the fish when the functioning of the protein was stopped. This helped in confirming that the protein in question does the same functions in fish and humans, ” she says.Since zebrafish commonly has two copies of many human genes, the researchers first checked if one or both the genes were functional and equivalent to the human gene that causes the disorder. “We found Ep300a gene was active and functional while Ep300b was not, ” says Prof. Tapas K. Kundu from the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, the other corresponding author. The Ep300a gene is responsible for producing a protein (Ep300) that opens up the DNA.“The protein Ep300 is evolutionarily conserved from fish to humans. Though the Ep300 gene has been earlier identified in fish, its function was not known, ” says Prof. Kundu.Reversal of effectsLike in the case of fish treated with chemicals manifesting the disorder, fish mutants that lacked the Ep300a gene too exhibited defects very similar to those seen in humans.“When we introduced excess amount of a tiny portion of the Ep300a protein in the mutants, the craniofacial deformities became less severe [mutants had severed craniofacial deformities] and pectoral fins in the fish became normal, ” she says.But neuronal defects were not reversed, even partially. “It might be because only a portion of the protein was put into the fish. Probably, that potion isn’t sufficient to compensate for the loss of the whole protein, ” she explains.“It’s proof-of-concept that just a piece of the protein is sufficient to reverse some defects, even if only partially, in zebrafish, ” Dr. Sachidanandan says.Alternatively, the researchers used two small molecules to reverse the defects. If the protein Ep300 is responsible for opening the DNA, there are other proteins that are responsible for closing the DNA.The two molecules were found from a screen of compounds well known for their ability to inhibit proteins responsible for closing the DNA.Like in the case when excess amount of Ep300 protein was introduced, both the molecules could partially restore facial defects but not the neuronal defects.“Introducing excess amount of a portion of the ep300 protein showed greater rescue of deformities than the small molecules, ” says Aswini Babu from IGIB and first author of the paper. “But rescuing the deformities using small molecules is a relatively easier and better option.”
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With cryo-electron microscope, India hopes to join the revolution sweeping across the world of medicineBy Hari Pulakkat, ET Bureau | Updated: Feb 12, 2018, 08.06 PM ISTAdvantage BioThe Bengaluru bio cluster has two additional institutions: the National Centre for Biological Sciences (NCBS) and the Centre for Cellular and Molecular Platforms (C-Camp). C-Camp is also an incubator of biology startups, some of which need to solve protein structures regularly for their work. The first company to use the cryo-EM facility is Bugworks, which is developing a new generation of drugs against antibiotic-resistant bacteria.Bugworks already has two drug candidates that aim to stop the bacteria from making copies of itself. They target the proteins responsible for unwinding the DNA in the bacteria, thereby not letting it duplicate itself. Drug companies like Bugworks need to know how a drug candidate binds to its target protein, and the cryo-EM will provide an image of the drug-protein complex easily.2“We use cryo-EM to optimise the next generation of drugs, ” says Santanu Datta, chief scientific officer, Bugworks. “X-ray crystallography will provide only a static picture.” At the Indian Institute of Science (IISc), a few kilometres from the bio cluster, assistant professor Tanveer Hussain is preparing to use the microscope for his research on protein synthesis. Hussain had used the cryo-EM in Ramakrishnan’s lab at Cambridge, while working on the initial steps of protein synthesis. He will soon get a smaller cryo-EM at IISc, which will be used for screening samples to be taken to the larger one at InStem.Scientists in other institutions are preparing to use it too. The Department of Biotechnology will fund a few smaller cryo-EMs at Pune, Faridabad and IIT-Delhi. “The cryomicroscope should be seen as a symbol of India’s entry into microscopy, ” says K Vijay-Raghavan, former secretary, DBT. India could amplify the benefits of the investment through technology development, especially in big data techniques. The microscope is evolving rapidly, and future versions will have deep reach while current versions will get cheaper.The technology parts of the cryo-EM — the electron gun, the detector, computation and so on — improved gradually over the years but made a quantum jump around 2012-13. This improvement made scientists move to the field in droves in the last three years. Henderson, who played a key role in developing the cryo-EM, has a few ideas about the immediate future of the technology. “We expect improvements of a factor of 20 in the information content of each image in two to three years, ” says Henderson. This means that you can get contemporary images with onetwentieth the effort, or make the same effort and get images that are 20 times better.This future excites scientists, and structural biologists using other methods are moving into the new field. So much so that companies that make the microscopes — the Bengaluru device was made by ThermoFisher — cannot make them fast enough. “It is a very exciting time, ” says Henderson. India is joining the bandwagon a bit late, but not too late.
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